The worldwide obesity epidemic, and an array of obesity-related diseases, particularly diabetes and cardiovascular diseases, have become a major public health threat in the 21st century. Obesity is characterized as excess expansion of adipose tissue, and studies in the last fifteen years have established that adipose tissue is an endocrine organ controlling systemic metabolism via secreted hormones (adipokines) and cytokines. But it remains incompletely understood how nutrient overload causes altered expression and secretion of adipocytokines, which lead to metabolic deterioration. In this project, we are using CHIP-sequencing to systemically investigate a few key epigenetic regulators in diet-induced obese mice and plan to examine their potential functions as nutrient sensors. At the same time, we are also utilizing RNA-sequencing to perform non-biased transcriptome screens of metabolic tissues and identify the subset that is differentially expressed in dietary or genetic obesity. Correlation study will then be performed to determine the potential co-regulation of gene expression and epigenetic landscape. The physiological functions of identified loci in metabolic regulation will be verified by genetic mouse models, and pathological significance investigated using samples of obese and diabetic patients. These studies will provide insights into epigenetic regulation of metabolic responses and also help identify novel pathways that could serve as potential therapeutic targets against obesity, diabetes and other metabolic diseases.